Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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    Molecular assessment of muscle health and function : The effect of age, nutrition and physical activity on the human muscle transcriptome and metabolom
    Hangelbroek, Roland W.J. - \ 2017
    Wageningen University. Promotor(en): A.H. Kersten; C.P.G.M. de Groot, co-promotor(en): M.V. Boekschoten. - Wageningen : Wageningen University - ISBN 9789463437103 - 205
    muscles - age - nutrition - physical activity - transcriptomes - metabolomes - elderly - creatine - phosphocreatine - vitamin d - atrophy - spieren - leeftijd - voeding - lichamelijke activiteit - transcriptomen - metabolomen - ouderen - creatine - fosfocreatine - vitamine d - atrofie

    Prolonged lifespan and decreased fertility will lead to an increased proportion of older adults in the world population (population aging). An important strategy to deal with population aging has been to promote healthy aging; not only to prevent mounting health care costs, but also to maintain independence and quality of life of older populations for as long as possible. Close to the opposite of the healthy aging is frailty. A major component of (physical) frailty is sarcopenia: age-related loss of muscle mass. Decreased muscle size and strength has been associated with a wide variety of negative health outcomes, including increased risk of hospitalization, physical disability and even death. Therefore, maintaining muscle size and strength is very important for healthy aging. Nutrition and physical activity are possible strategies to maintain or even improve muscle function with age.

    The effect of nutrition, age, frailty and physical activity on the function of skeletal muscle is complex. A better understanding of the molecular mechanisms involved can provide new insights in potential strategies to maintain muscle function over the life course. This thesis aims to investigate these mechanisms and processes that underlie the effects of age, frailty and physical activity by leveraging the sensitivity and comprehensiveness of transcriptomics and metabolomics.

    Chapter 2 and 3 describe the effects of age, frailty and resistance-type exercise training on the skeletal muscle transcriptome and metabolome. Both the transcriptome and metabolome show significant differences between frail and healthy older adults. These differences are similar to the differneces between healthy young men and healthy older adults, suggesting that frailty presents itself as a more pronounced form of aging, somewhat independent of chronological age. These age and frailty related differences in the transcriptome are partially reversed by resistance-type exercise training, in accordance with the observed improvement in muscle strength. Regression analysis revealed that the protocadherin gamma gene cluster may be important to skeletal muscle function. Protocadherin gamma is involved in axon guidance and may be upregulated due to the denervation-reinnervation cycles observed in skeletal muscle of older individuals. The metabolome suggested that resistance-type exercise training led to a decrease in branched-chain amino acid oxidation, as shown by a decrease in amino acid derived carnitines. Lastly, the blood metabolome showed little agreement with the metabolome in skeletal muscle, indicating that blood is a poor read-out of muscle metabolism.

    We assessed the effect of knee immobilization with creatine supplementation or placebo on the skeletal muscle transcriptome and metabolome in chapter 4. Knee immobilization caused muscle mass loss and strength loss in all participants, with no differences between creatine and placebo groups. Knee immobilization appeared to induce the HDAC4-myogenin axis, which is primarily associated with denervation and motor neuron diseases. The metabolome showed changes consistent with the decreased expression of energy metabolism genes. While acyl-carnitine levels tended to decrease with knee immobilization, one branched-chain amino acid-derived acyl carnitine was increased after knee immobilization, suggesting increased amino acid oxidation.

    Vitamin D deficiency is common among older adults and has been linked to muscle weakness. Vitamin D supplementation has been proposed as a strategy to improve muscle function among older populations. In chapter 5, supplementation with vitamin D (calcifediol, 25(OH)D) is investigated as nutritional strategy to improve muscle function among frail older adults. However, we observed no effect of vitamin D on the muscle transcriptome. These findings indicate the effects of vitamin D supplementation on skeletal muscle may be either absent, weak, or limited to a small subset of muscle cells.

    Transcriptomic changes due to different forms of muscle disuse are compared in chapter 6 (primarily knee immobilization and bed rest). The goal was to determine the similarities and differences among various causes of muscle atrophy in humans (primarily muscle disuse). Both knee immobilization and bed rest led to significant changes in the muscle transcriptome. However, the overlap in significantly changed genes was relatively small. Knee immobilization was characterized by ubiquitin-mediated proteolysis and induction of the HDAC4/Myogenin axis, whereas bed rest revealed increased expression of genes of the immune system and increased expression of lysosomal genes. Knee immobilization showed the highest similarity with age and frailty-related transcriptomic changes. This finding suggests that knee immobilization may be the most suitable form of disuse atrophy to assess the effectiveness of strategies to prevent age-related muscle loss in humans.

    The transcriptome and metabolome are incredibly useful tools in describing the wide array of biological systems within skeletal muscle. These systems can be modulated using physical activity (or lack thereof) as well as nutrition. This thesis describes some of these processes and highlights several unexplored genes and metabolites that may be important for maintaining or even optimizing muscle function. In the future, it may be possible to optimize both exercise and nutrition for each individual using these techniques; or even better, cheaper and less invasive alternatives.

    Mechanisms of vegetative propagation in bulbs : a molecular approach
    Moreno-Pachón, Natalia - \ 2017
    Wageningen University. Promotor(en): R.G.H. Immink, co-promotor(en): H.W.M. Hilhorst. - Wageningen : Wageningen University - ISBN 9789463437011 - 178
    ornamental bulbs - tulipa - lilium - vegetative propagation - flowering date - gene regulation - genes - transcriptomes - dna sequencing - regeneration - shoot apices - bloembollen - tulipa - lilium - vegetatieve vermeerdering - bloeidatum - genregulatie - genen - transcriptomen - dna-sequencing - verjonging - scheuttoppen

    Vegetative propagation is very important for the survival of species with long juvenile and adult vegetative phases, as it is the case for bulbous plants. Bulbous plants are ornamental geophytes with a bulb as an underground storage organ. Among flower bulbs, tulip and lily are the two commercially leading plants in The Netherlands. Tulip propagates vegetatively via axillary bud outgrowth, while lily propagates via adventitious bulblet formation. The vegetative propagation rate in tulip is very low due to the limited amount of axillary buds that will grow successfully. Moreover, tulip is very recalcitrant to in vitro regeneration. On the other hand, lily propagates efficiently via adventitious bulblet formation, either naturally from the underground portion of the stem of the apical bud, or artificially from detached bulb scales.

    This thesis study aimed to understand how axillary bud outgrowth is controlled in tulip bulbs and how regeneration capacity is established in lily bulb scales. As a first step towards these goals, the state of the art of the molecular control of sexual and vegetative reproduction was reviewed for model species. Moreover, two approaches, “bottom-up” and “top-down”, to transfer the knowledge from model to non-model species were described (Chapter 2). In short, the “bottom-up” approach usually goes from individual genes to systems, assuming conservation of molecular pathways and using sequence homology searches to identify candidate genes. ”Top-down” methodologies go from systems to genes, and are based on large scale transcriptome profiling via e.g. microarrays or RNA sequencing, followed by the identification of associations between phenotypes, genes, and gene expression patterns and levels.

    Next (Chapter 3), two sets of high quality transcriptomes, one for tulip and one for lily were generated from a collection of several tissues using the Illumina HiSeq 2000 platform. Several assembly filtering parameters were applied, to highlight the limitations of stringent but routinely used filtering in de novo transcriptome assembly. The final created transcriptomes were made publicly available via a user friendly Transcriptome browser (http://www.bioinformatics.nl/bulbs/db/species/index) and their usefulness was exemplified by a search for all potential transcription factors in lily and tulip, with special focus on the TCP transcription factor family.

    One TCP member was of special interest because it has proven to integrate several pathways that control axillary bud outgrowth in a wide range of species. It is called TEOSINTE BRANCHED 1 (TB1) in monocots and BRNACHED 1 (BRC1) in dicots. A Tulipa gesneriana TB1 transcript was identified from the generated transcriptome and subsequently, tulip axillary bud outgrowth was studied through a “bottom-up” approach (Chapter 4). The degree of axillary bud outgrowth in tulip determines the success of their vegetative propagation. However the number of axillary meristems in one bulb is low –six on average– and not all of them seem to have the same growth capacity. The combination of physiological and targeted molecular experiments indicated that the first two inner located buds do not seem to experience dormancy (assessed by weight increase and TgTB1expression) at any point of the growth cycle, while mid-located buds enter dormancy by the end of the growing season. Moreover it was shown that TgTB1 expression in tulip bulbs can be modulated by sucrose, cytokinin and strigolactone, just as it has been reported for other species. However, the limited growth of mid-located buds even when their TgTB1 expression was naturally or artificially downregulated, pointed at other factors, probably physical, inhibiting their growth.

    Next, the remarkable regeneration capacity of lily by initiating de novo shoot meristems from excised bulb scales without the addition of exogenous hormones or growth regulators was studied using a “top-down” approach (Chapter 5). An extensive and comprehensive transcriptome set was generated from lily bulb scales in a time-series using two cultivars and two explant types, all differing in regeneration capacity. This set up provided first insight in the key molecular process underlying pro-meristem induction and meristem initiation in lily. We found that wounding activates a very fast regeneration response, probably mediated by APETALA2/ETHYLENE RESPONSIVE FACTORS (AP2/ERF,) such as LoERF115 and WOUND INDUCED DEDIFFERENTIATION 2 (LoWIND2), which in turn might mediate polar auxin re-distribution, cell proliferation and de-differentiation. Moreover, the timing and level of induction of shoot meristem regulators, such as ENHANCER OF SHOOT REGENERATION 2 (LoESR2) and SHOOT MERISTEMLESS (LoSTM) correlated with the regeneration capacity of the scale.

    Regardless the regeneration capacity of the different explants e.g. cultivar or position within the scale, regeneration occurs at the proximal-adaxial side of the bulb scale, right on top of the excision line. Thus the possible cellular and physiological factors granting lily bulb scales their competence to regenerate was investigated (Chapter 6). We found that the adaxial parenchyma tissue seems to be more competent than the abaxial tissue, partially because of higher number of secondary veins and larger cell population than the abaxial parenchyma region. It was proposed that upon explant excision, the polar auxin transport is disrupted, creating an auxin maximum at the excision line, which might create a gradient of cell divisions favouring the adaxial parenchyma tissue. The direction of this cell division gradient proved to be negatively affected by the absence of the adaxial epidermis. Moreover, explants without epidermis reduced dramatically their regeneration capacity, and lost the typical proximal-adaxial orientation of regeneration. Thus, a better understanding of the composition and physiology of the epidermis in lily bulb scales is essential to identify the regeneration stimulating signals originating from this tissue layer in Lilium sp.

    Finally in Chapter 7, integration of all the results was done and I addressed how this may contributes to the fundamental and applied understanding of vegetative propagation in bulbous plants. Also, some challenges are discussed, for example, the complexity in the architecture of tulip bulbs and how this influences ways for improving its rate of axillary bud outgrowth. The challenge to prove the findings of this thesis through functional analysis is also discussed and the possibility of using transient virus-induced gene silencing is highlighted. Moreover, the potential of lily bulb scales as a model system to study some aspects of de novo regeneration, as well as to study the recalcitrance of in vitro propagation is highlighted, supporting the idea that more “omics” data and biotechnological tools for bulbous plant research are necessary.

    Akkermansia species : phylogeny, physiology and comparative genomics
    Ouwerkerk, J.P. - \ 2016
    Wageningen University. Promotor(en): Willem de Vos, co-promotor(en): Clara Belzer. - Wageningen : Wageningen University - ISBN 9789462577411 - 178
    akkermansia - akkermansia muciniphila - gastrointestinal microbiota - phylogeny - physiology - genomics - dna sequencing - nucleotide sequences - transcriptomes - antibiotic resistance - genome annotation - akkermansia - akkermansia muciniphila - microbiota van het spijsverteringskanaal - fylogenie - fysiologie - genomica - dna-sequencing - nucleotidenvolgordes - transcriptomen - antibioticaresistentie - genoomannotatie

    The gastrointestinal tract is lined with a mucus layer, which is colonized by a distinct mucosal microbial population. The anaerobic gut bacterium Akkermansia muciniphila is a well-described member of the mucosal microbiota and has been shown to be a human gut symbiont. In the mucus layer this gut symbiont is likely exposed to the oxygen that diffuses from mucosal epithelial cells. We showed that A. muciniphila has an active detoxification system to cope with reactive oxygen species and can use oxygen for respiration at nanomolar oxygen concentrations, with cytochrome bd as terminal oxidase.

    Until now, the type strain A. muciniphila MucT was the only cultured representative of this species. We isolated and characterized six new A. muciniphila strains from faecal samples of four different human subjects. These A. muciniphila strains showed minimal genomic and physiologic divergence while retaining their mucin degrading and utilisation capacities. Apart from the human gastrointestinal tract, we detected Akkermansia species in intestinal samples of numerous mammals. An additional ten new A. muciniphila strains were isolated from seven different mammalian species and showed high genomic and physiologic similarity to type strain A. muciniphila MucT. Apart from Akkermansia species, other Verrucomicrobia were identified within the gastrointestinal tract of non-human mammals. Furthermore, we obtained an Akkermansia isolate from the reticulated python, which had a similar mucin degrading capacity as the human strain A. muciniphila MucT but showed more efficient galactose utilization. On the basis of further phylogenetic, physiological, and genomic characterisations, strain PytT was found to represent a novel species within the genus Akkermansia, for which the name Akkermansia glycaniphilus sp. nov. is proposed.

    Overall, A. muciniphila strains isolated from intestinal samples of human and other mammals show very limited genomic and physiologic divergence. This together with the widely-spread global presence of A. muciniphila and the dependence on mucin for optimal growth, points towards a conserved symbiosis. This conserved symbiosis might be indicative for the beneficial role of this organism in respect to the host metabolic health. This is in line with the observation that A. muciniphila has been negatively associated with obesity and its associated metabolic disorders.

    In mice, treatment with viable A. muciniphila cells reversed high-fat diet-induced obesity. We described a scalable workflow for the preparation and preservation of high numbers of viable cells of A. muciniphila under strict anaerobic conditions for therapeutic interventions. Moreover, we developed various quality assessment and control procedures aimed to ensure the use of viable cells of A. muciniphila at any location in the world. These viable cells were used in a pilot study in humans in which no adverse events were observed. This is promising for future applications of A. muciniphila as a new therapeutic, leading towards the potential treatment of unhealthy states of the microbiota.

    Mucus and gut barrier in health and disease
    Sovran, B. - \ 2015
    Wageningen University. Promotor(en): Jerry Wells; P. de Vos, co-promotor(en): J. Dekker. - Wageningen : Wageningen University - ISBN 9789462574892 - 233
    slijm - spijsverteringskanaal - darmen - muizen - probiotica - eilandjes van peyer - colitis - transcriptomen - immunohistologie - veroudering - geslacht (sex) - homeostase - gezondheid - ziekten - mucus - digestive tract - intestines - mice - probiotics - peyer patches - colitis - transcriptomes - immunohistology - senescence - sex - homeostasis - health - diseases

    This publication describes his work as a PhD student in the Host-Microbe Interactomics Chair group at Wageningen University within the Gastrointestinal Health theme. It has been completed under the supervision of Prof. Dr Jerry M Wells, Dr Jan Dekker and the TIFN project leader, Prof. Dr Paul de Vos.

    Mucus serves as a protective layer between the intestinal content and the intestinal wall. It facilitates the passage of the luminal content through the intestine, reducing the risk of mechanical damage to the intestinal epithelium. The overarching goal of this thesis was to investigate the role of mucus in the maintenance of the intestinal immune barrier and the effects of ageing and gender differences on mucus production and the gut barrier.

    We found by using a mouse model that decreased mucus production leads to changes in microbiota and mucosal stress responses, without the appearance of pathology, demonstrating the importance of mucus in intestinal homeostasis. The mucus barrier was shown to deteriorate during aging but this could be prevented with specific probiotics. Furthermore gender-specific differences in the effects of ageing on the mucosal barrier were found. Increased knowledge on these mechanisms might contribute significantly to disease prevention and treatment, for instance by optimizing gender-specific dietary and pharmacological requirements.

    The study presented in this thesis was performed within the framework of Top Institute Food and Nutrition, within the GH002 project.

    Molecular and physiological assessment of metabolic health : adipose tissue, transcriptome analysis and challenge tests
    Duivenvoorde, L.P.M. - \ 2015
    Wageningen University. Promotor(en): Jaap Keijer, co-promotor(en): Evert van Schothorst. - Wageningen : Wageningen University - ISBN 9789462573017 - 186
    muizen - metabolisme - gezondheid - vetweefsel - transcriptomen - stofwisselingsstoornissen - fysiologie - laboratoriumdieren - mice - metabolism - health - adipose tissue - transcriptomes - metabolic disorders - physiology - laboratory animals

    Summary of main findings

    Maintenance of metabolic health not only ensures that energy is made available in times of need and stored in times of excess, but also prevents resistance to nutritional cues, ectopic lipid accumulation and dysfunction of metabolic organs. The proportion of humans that is at risk for reduced metabolic health increases worldwide due to the current epidemic of obesity and the increase in both mean and maximum life span. Better understanding of the various factors that influence metabolic health may offer opportunities to fight this threat to human health. This thesis aims to assess metabolic health using transcriptome analysis and non-invasive challenge tests. Special focus is on the development and validation of InCa-based non-invasive challenge tests. In most chapters of this thesis white adipose tissue (WAT) formed the major organ of interest because of its key role in whole-body energy homeostasis. WAT function was, among others, studied with whole-genome gene expression analysis, which, compared to single parameter analysis, extends the scale and depth of understanding biological processes.

    Metabolic health was also quantified as metabolic flexibility, with the use of non-invasive, indirect calorimetry (InCa) based challenge tests. One of the InCa based challenge tests described in this thesis, the oxygen restriction (OxR) challenge, is a novel approach to investigate metabolic flexibility in mice. In each study, OxR was applied acute ([O2] reduction within 30 minutes) and for a short period of 6 hours in fasted mice. The other two InCa-based challenge tests: fasting and re-feeding and fasting and glucose consumption are nutrient-based and were described previously, although in different formats and settings.

    In chapter 2 we demonstrate that dietary restriction on a high-fat diet (HF-DR) improves metabolic health of mice compared with mice receiving the same diet on an ad libitum basis (HF-AL). Already after five weeks of restriction, the serum levels of cholesterol and leptin were significantly decreased in HF-DR mice, whereas their glucose tolerance and serum adiponectin levels were increased. The body weight and measured serum parameters remained stable in the following 7 weeks of restriction, implying metabolic adaptation. To understand the molecular events associated with this adaptation, we analysed gene expression in WAT with whole genome microarrays. HF-DR strongly influenced gene expression in WAT; in total, 8643 genes were differentially expressed between both groups of mice, with a major role for genes involved in lipid metabolism and mitochondrial functioning. DR also increases mitochondrial density in WAT. These results show that WAT, indeed, has an important role in the improvement of metabolic health of dietary restricted mice and suggest that the development of substrate efficiency plays an important role in the observed changes in health status. Finally, mitochondrial density might be used as a marker for WAT health status.

    Chapter 3 shows how indirect calorimetry can be used to noninvasively assess metabolic and age-related flexibility in mice. In this study, we tested the sensitivity and response stability over time of three InCa-based treatments in old versus adult mice. For the first treatment, diurnal patterns of respiratory exchange ratio were followed for 24 hours under standard conditions. For the second and third treatment, which were both based on a challenge approach, mice were fasted and either received a glucose bolus to test switch-effectiveness from fat to glucose oxidation (Treatment 2), or were exposed to oxygen restriction (OxR, Treatment 3) in the InCa system, which was introduced as a novel approach to asses metabolic flexibility. Opposite to the mice that were dietary restricted (chapter 2), aging appeared to increase adiposity and decrease WAT mitochondrial density, which further suggests that WAT mitochondrial density might be used as a marker for WAT health. We observed that the test results of the first treatment were not stable between test periods, possibly because of behavioural differences within the group of old mice between both measurements. For the second treatment, no differences between groups were observed. With Treatment 3, however, stable significant differences could be detected: old mice did not maintain reduced oxygen consumption under OxR during both measurements, whereas adult mice did. Further biochemical and gene expression analyses showed that OxR affected glucose and lactate homeostasis in liver and WAT of adult mice, supporting the observed differences in oxygen consumption. This was the first study to show that InCa analysis of the response to OxR is a sensitive and reproducible treatment to noninvasively measure age-impaired metabolic health in mice. Evaluation of metabolic health under non-challenged conditions may be confounded by behavioural-induced variation between animals

    The study described in chapter 4 followed up on the promising results that were obtained with the OxR challenge in chapter 3. In this study we tested whether OxR can also be used to reveal diet-induced health effects in an early stage. Early detection of diet-induced health effects might shorten animal experiments and reduce costs and age-related variation. Timely identification may increase options for reversal. Mice were exposed to a low-fat (LF) or high-fat (HF) diet for only 5 days, after which they were exposed to OxR or remained under normoxic conditions. The response to OxR was assessed by calorimetric measurements, followed by analysis of gene expression in liver and WAT. A novelty described in this chapter was the analysis of serum markers for protein glycation and oxidation, to detect differences in the response to OxR between LF and HF mice. Although HF feeding increased body weight, HF and LF mice did not differ in indirect calorimetric values under normoxic conditions and in a fasting state. Exposure to OxR however, increased oxygen consumption and lipid oxidation in HF mice versus LF mice. Furthermore, OxR induced gluconeogenesis and an antioxidant response in the liver of HF mice, whereas it induced de novo lipogenesis and an antioxidant response in eWAT of LF mice, indicating that HF and LF mice differed in their adaptation to OxR. OxR also increased serum markers of protein glycation and oxidation in HF mice, whereas these changes were absent in LF mice. From this study we concluded that OxR is a promising new method to test food products on potential beneficial effects for metabolic health.

    The study described in chapter 5 aimed to assess differences in metabolic health of mice on iso-caloric diets differing in fatty acid composition using the OxR challenge. We also implemented a fasting and re-feeding challenge. One diet, the HFpu diet, predominantly contained poly-unsaturated fatty acids (PUFAs), which are considered to be healthier than saturated fatty acids (SFAs) that mainly made up the fat component of the second diet, the HFs diet. Since health effects of fatty acids also depend on the ratio of dietary omega-6 to omega-3 PUFAs (n6/n3 ratio), this ratio was kept similar between both diets. Mice received the isocaloric high-fat diets for six months, during and after which several biomarkers for health were measured. We found that HFpu and HFs diets only induce minor differences in static health markers: HFpu and HFs mice did not differ in body weight, total adiposity, adipose tissue health, serum adipokines, whole body energy balance, or circadian rhythm. HFpu and HFs mice also had a similar glucose tolerance, even though HFs mice had more triglycerides in liver and skeletal muscle and larger adipocytes in the eWAT depot. Interestingly, HFs mice were less flexible in their response to both fasting and re-feeding and OxR, which shows the relevance and sensitivity of InCa-based challenge tests. We concluded that InCa-based challenge tests are a valuable contribution to the analysis of metabolic health in mice. Challenge tests in the InCa system may, furthermore, reveal relevant consequences of small changes in metabolic health status, such as adipocyte hypertrophy or ectopic lipid storage.

    Chapter 6 describes an in-depth study to the response to OxR both at whole body level using InCa and serum metabolomics (amino acids and (acyl)carnitines) and at WAT level using transcriptomics and the analysis of amino acid and (acyl)carnitine levels. Serum and tissue amino acids levels indicate the level of protein catabolism and certain amino acids are, typically, increased in obese individuals. Serum and tissue (acyl)carnitine levels indicate the rate and completeness of mitochondrial fatty acid oxidation; serum acylcarnitine levels are significantly increased in individuals that suffer from ambient oxygen restriction. The metabolic adaptation to OxR was studied in diet-induced moderately obese mice that received a high-fat diet (HFpu diet, as in chapter 5) for 6 weeks, which is expected to lead to WAT expansion and possibly to reduce oxygen availability in WAT. We found that OxR reduced mitochondrial oxidation at whole-body level, as shown by a reduction in whole-body oxygen consumption and an increase in serum long-chain acylcarnitine levels. WAT did not seem to contribute to this serum profile, since only short-chain acylcarnitines were increased in WAT and gene expression analysis indicated an increase in mitochondrial oxidation, based on coordinate down-regulation of Sirt4, Gpam and Chchd3/Minos3. In addition, OxR did not induce oxidative stress in WAT, but increased molecular pathways involved in cell growth and proliferation. OxR increased levels of tyrosine, lysine and ornithine in serum and of leucine/isoleucine in WAT. This study shows that OxR limits oxidative phosphorylation at whole-body level, but in WAT compensatory mechanisms seem to operate. The down-regulation of the mitochondria-related genes Sirt4, Gpam, and Chchd3 may be considered as a biomarker profile for WAT mitochondrial reprogramming in response to acute exposure to limited oxygen availability.

    To conclude, the work presented in this thesis provides more insight in the analysis of metabolic health in mice with the use of transcriptome analysis and InCa-based challenge tests. We show that non-invasive tests using the InCa-system are more likely to reveal differences in metabolic flexibility than invasive challenge tests, such as the oral glucose tolerance test. Furthermore, we show that the challenge approach is more sensitive than analysis of metabolic health under non-challenged (free-feeding) conditions. Transcriptome analysis proved to be very valuable to provide in-depth molecular understanding of the mechanisms underlying reduced or improved metabolic health. Ideally, transciptomic or metabolomic approaches should be integrated with InCa-based challenge tests to further extent physiological understanding of diet-induced health effects.

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